1. Field of the Disclosure
The invention relates to an active-ingredient-containing matrix-controlled transdermal therapeutic system for the use of pramipexole, ropinirole, pharmaceutically acceptable salts thereof or pharmaceutically acceptable derivatives thereof.
2. Brief Description of the Related Technology
Pramipexole and ropinirole are used for the treatment of Parkinson's disease. As a dopamine agonist, pramipexole [2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole] binds with high selectivity and specificity to the D2 and D3 receptors. Owing to its stimulating effect on the dopamine receptors in the corpus striatum, pramipexole produces a reduction in Parkinson's tremors. When administered orally, the daily dose is approximately from 1.5 to 4.5 mg with a bioavailability of 90%. However, the administration of even small amounts of pramipexole is associated with considerable side-effects in the patient. Ropinirole [4-(2-di-n-propylaminoethyl)-2-(3H)-indolone] acts as a dopamine agonist with high selectivity on the D2 receptors. The daily dose is from 0.3 to 30 mg when administered orally. The bioavailability is 50%.
By means of a transdermal therapeutic system it is possible to circumvent the side-effects that occur in the case of oral administration of pramipexole or ropinirole. Transdermal administration furthermore has the advantage that the active ingredient, after permeation through the skin, has a direct systemic action, as a result of which a constant blood plasma level can be guaranteed. Hepatic metabolism of the active ingredient is also circumvented, that is to say, the burden on the liver is relieved. Gastrointestinal side-effects are avoided. The use of patches that retain their full effectiveness for several days, which in contrast to oral administration is simple and convenient, is an advantage for the patient. Since the system is applied externally, it can fulfil its intended function for a very long time without being changed.
There is already known from EP-B1-0 428 038 a transdermal system having a content of pramipexole and                a) an active-ingredient-impermeable backing layer which is at the same time constructed as a covering plaster,        b) an active-ingredient-containing reservoir (preferred carrier for the active ingredient is an emulsion-polymerised polyacrylate of the type Eudragit NE 30 DR produced by Röhm GmbH, Darmstadt) and        c) a peel-off protective film (release liner).        
Owing to surfactants or plasticisers and surface-active substances used in an emulsion-polymerised polyacrylate, a TTS produced according to EP-B1-0 428 038 does not exhibit sufficient stability of the active ingredient. In that matrix, pramipexole decomposes very rapidly, with discoloration occurring. In addition, the active ingredient crystallises out. That patch does not, therefore, have sufficient stability in storage.
WO 99/49853 proposes a moisture-activatable transdermal therapeutic system in which ropinirole hydrochloride is incorporated in a matrix together with an activator that gives a basic reaction in water, such as, for example, hydrated sodium silicate. The unstable ropinirole base, which has good permeation properties, is released from the stable ropinirole hydrochloride, which has a poor permeation capacity, only on the skin as a result of the admission of moisture. The release of the active ingredient and hence also the permeation of the active ingredient is therefore dependent on the moisture of the skin, which may possibly lead to irregular permeation rates and hence to fluctuating blood levels.
Matrix-TTSs having a content of ropinirole are described in WO 96/39136 and WO 97/11696.
In WO 96/39136, a TTS having a reservoir consisting of ropinirole base and lactose in a hydrogel (water, glycerine, polyvinyl alcohol, polyvinylpyrrolidone) is used.
WO 97/11696 describes a patch having a matrix consisting of ropinirole base, propylene glycol monolaurate and silicone adhesive.
Since ropinirole base is unstable, the above-mentioned systems would probably not be stable in storage for long.